In recent years, there is an increasing demand for developing self-injectable antibody-containing formulations for subcutaneous injection according to medical needs. Designing antibody-containing formulations for subcutaneous injection makes it necessary to increase the antibody concentration in the administered solution, since a single doses of antibody are very high (about 100 to 200 mg) and the injection volume for subcutaneous injection is generally limited.
Highly-concentrated antibody-containing solutions tend to form highly viscous solutions by themselves due to intermolecular interactions and macromolecular protein characteristics. Furthermore, degradation phenomenon such as aggregation becomes problematic when proteins are stored as highly-concentrated solutions, and thus, this degradation must be prevented. In particular, highly-concentrated antibody-containing solutions tend to form aggregates during freeze-thawing, or when stored in liquid or frozen conditions for a long time (Non-patent Documents 1 and 2).
To date, such highly-concentrated antibody-containing formulations are generally prepared by conventional lyophilizing concentration method (Patent Document 1), which is a method for stabilizing highly-concentrated antibody-containing formulations. In the method, highly-concentrated antibody-containing formulations are obtained by lyophilizing an antibody solution of a relatively low concentration and dissolving in a smaller volume of water than the volume before lyophilization. In this case, the increased viscosity of dissolved formulations is of concern because a cryoprotectant such as sugar must be added to obtain lyophilized formulations.
In that aspect, this problem can be avoided when a liquid formulation is prepared without lyophilization. However, as described above, highly-concentrated antibody-containing liquid formulations tend to form aggregates. Nonetheless, such formulations are highly demanded because antibody-containing liquid formulations are easier to handle than lyophilized formulations, and can be readily formulated into prefilled syringe formulations.
There have been various studies to stabilize highly-concentrated antibody-containing liquid formulations (Non-patent Documents 1-4). Histidine buffer and arginine have been reported to be useful as a buffer and a stabilizer, respectively, in antibody-containing liquid formulations (Patent Documents 2, 3, 4, 5, and 6). The histidine buffer is commonly used in the form of hydrochloric acid salt. Recently, it has been reported that histidine-acetate shows a higher stabilization effect than histidine hydrochloride and thus acetic acid is useful as a counter ion species in histidine buffer (Patent Document 6). Meanwhile, arginine as a stabilizer has been generally used in the form of arginine hydrochloride. However, in some cases, sufficient stability is not obtained when hydrochloric acid or acetic acid is used as a counter ion species to histidine or arginine. Thus, more superior counter ion species are needed.